Energy metabolism in the body is controlled by insulin produced in pancreatic β cells. Insulin acts on peripheral tissues or cells and plays an important role in controlling blood sugar levels by promoting the assimilation of sugar from the blood. However, when a high caloric meal is taken continuously and insulin sensitivity in cells decreases, elevation of blood glucose levels and oversecretion of insulin proceed simultaneously. As a result, pancreatic β cells are exhausted to become dysfunctional and develop diabetes or obesity.
Insulin secretion is regulated by various hormones. In particular, glucagon-like peptide-1 (GLP-1) that is produced and secreted in the gastrointestinal tract is considered important. GLP-1 is a peptide hormone with a molecular weight of approximately 4,000 and produced mainly in the L-cells of the small intestine. It has been revealed that GLP-1 has activities of promoting insulin secretion from β cells, suppressing gastric peristalsis and digestive absorption, suppressing appetite, bulimia or the like and is thus effective for the treatment or prevention of diabetes or obesity. It is known that GLP-1 production capacity decreases in diabetes and obesity. If GLP-1 production can be promoted in the clinical entities of these diseases, it is expected to lead to the treatment and prevention of diabetes or obesity The production of GLP-1 in the L cells is promoted by uptake of a variety of nutrition including carbohydrates, lipids, proteins, etc. However, compounds such as specific peptide components, etc. are rarely utilized as a GLP-1 secretion promoter.
Cholecystokinin (CCK) is a peptide hormone with a molecular weight of approximately 4,000, which is produced mainly in the L-cells of the duodenum and the small intestine, and promotes the secretion of bile and the secretion of pancreatic digestive juice. Physiological effects of CCK that are particularly noteworthy involve an activity of suppressing gastric emptying of food, an activity of promoting pancreatic enzyme secretion and an anorexigenic effect on food intake by a sense of satiation (Non-Patent Documents 1 and 2). In addition, there is also known an activity of promoting the secretion of insulin that is a glucoregulatory hormone (Non-Patent Documents 3 and 4). CCK has these activities or effects and is considered to be promising for the treatment or prevention of lifestyle-related diseases such as diabetes, obesity, pancreatitis, etc.
GLP-1 and CCK are peptides and are to be administered intravascularly by injecting GLP-1 and CCK, etc. to make them available for therapy, but such is not realistic due to the complicated daily administration and considerable expense. On the other hand, it is considered to use such a mechanism that endogenous GLP-1 and CCK are secreted from GLP-1 and CCK-producing cells in the small intestinal mucosa by proteins, peptides, amino acids, fatty acids, etc., of dietary constituents. That is, it has been desired to develop compounds or food materials having the GLP-1 and CCK secretion promoting activity.
On the other hand, a calcium sensing receptor (CaSR), which is also called a calcium receptor, transduces the receptor signals to regulate various in vivo functions. Thus, there is a possibility that substances having a CaSR agonist activity are useful for treating or preventing various diseases and also useful as kokumi-imparting agents. Patent Document 1 discloses a screening method for a kokumi-imparting substance and a kokumi-imparting agent containing a kokumi-imparting substance obtainable by the screening method. It has been found that a variety of low molecular peptides possess the CaSR agonist activity, and described that based on this finding, it has become possible to provide a kokumi-imparting agent capable of imparting “kokumi taste,” i.e., the taste that cannot be expressed only with five basic tastes of sweet, salty, sour, bitter and umami tastes, and the taste that enhances marginal tastes of the basic tastes described above, such as thickness, growth (mouthfullness), continuity and harmony.
Furthermore, it has been known from old that γ-glutamylanilide derivatives act as the substrate for γ-glutamyltransferase and can be used for enzyme activity measurements (Non-Patent Document 5, Patent Document 2). However, no publication discloses any relation to “calcium sensing receptor (CaSR) or G protein-coupled receptor,” “diabetes or obesity,” “promotion of GLP-1 secretion,” “promotion of CCK secretion,” “suppression of gastric emptying,” etc., which are characteristic features of the present invention.
On the other hand, cinacalcet or synthetic low molecular compounds analogous thereto as well as γ-glutamylpeptide derivatives including glutathione are known as compounds for activating CaSR (Patent Document 4, Non-Patent Documents 8 and 9). Among them, a part of the compounds are also known to have use as therapeutic agents for diabetes or obesity (Patent Document 5). However, these compounds are structurally different from the glutamic acid derivative of the present invention.
Also in some known compounds among 3-sulfonic acids, 3-carboxylic acids and 3-nitro derivatives, which are particularly preferred in the present invention, most of their utilities are focused on substrates in enzymatic activity measurements of γ-glutamyltransferase; antibacterial agents or antiallergic agents (Non-Patent Document 6 and Patent Document 3) and analysis reagents for mass spectrometry (Non-Patent Document 7) are only a few other known uses.
It is therefore expected to explore compounds with numerous variations having the CaSR agonist activity and provide more excellent preventive or therapeutic agents for diabetes or obesity.